tbuckley/cabot-search huggingface dataset:
Will Vasopressin 2 Receptor Antagonists Prevent Autosomal Dominant Polycystic Kidney Disease?
Authors: Vincente E. Torres, Xiaofang Wang, Qi Quian, Stefan T. Somlo, Peter Harris, Vincent Gattone
Journal: Journal of the American Society of Nephrology (2005)

Throughout the world, autosomal dominant polycystic kidney disease (ADPKD) accounts for 5 to 10% of patients who require renal replacement therapy. It therefore is a leading cause of ESRD. It is genetically heterogeneous. The two genes so far identified, PKD1 and PKD2, are thought to interact in renal cells, one major function being regulation of intracellular calcium. Grantham and colleagues (1,2) had postulated that increased cAMP concentrations result from altered intracellular calcium homeostasis and are involved in creating the proliferative and secretory phenotype characterizing cyst wall epithelial cells in contrast with the inhibitory effect of cAMP in the normal kidney cortex. Agonists that increase cellular cAMP, e.g., arginine vasopressin, prostaglandin E2, catecholamines, and cyst-activating factor, a neutral lipid isolated from cyst fluid (3), have the potential to stimulate cyst proliferation and fluid secretion into the cyst. In this context, it is of considerable interest that—in contrast to previous opinion—it is currently thought that the vast majority of the cysts stain for collecting duct markers and are derived from collecting ducts (4), the major target for arginine vasopressin in the nephron. It is also of note that a defect of urinary concentration is one of the earliest manifestations of ADPKD (5). In previous studies, inhibition of the vasopressin V2 receptor coupling with adenyl cyclase had interfered with formation and growth of cysts. This was seen in experimental models of renal cyst formation that were orthologous to human autosomal recessive PKD and nephronophthisis, respectively (6). The present study (7) carried this one step further by studying an animal model of ADPKD that is even more relevant to the most prevalent form of PKD in humans. The authors investigated Pkd−/tm1Som mice, which are orthologous to PKD2 in humans. In these animals, the molecular machinery of renal cAMP, aquaporin-2, and V2 receptor was upregulated. The V2 receptor antagonist OPC31260 was administered in the diet between 3 and 16 wk of age. This agent reduced renal cAMP, aquaporin-2, and the V2 receptors. Of note, however, treated animals also had lower kidney weight, blood urea nitrogen, cyst number, and markers of mitosis and apoptosis. Within the sensitivity of this animal model, no major side effects were noted. Obviously, at least in this animal model, the vasopressin V2 antagonist interfered with development and progression of ADPKD. V2 antagonists are studied extensively in hyponatremic states (heart failure, liver cirrhosis) and have a relatively good safety profile, presumably because of their high renoselectivity (8). The above experimental findings also make them hot candidates for controlled studies to interfere with the progression of ADPKD in humans.
Atrial Fibrillation Incidence Associated With Exposure to Anticancer Drugs Used as Monotherapy in Clinical Trials
Authors: Joachim Alexandre, Louis Boismoreau, Pierre-Marie Morice, Marion Sassier, Angélique Da-Silva, Anne-Flore Plane, Jonaz Font, Paul Milliez, Damien Legallois, Charles Dolladille
Journal: JACC CardioOncology (2023)

The incidence of atrial fibrillation (AF) associated with anticancer drugs in cancer patients remains incompletely defined.The primary outcome was the annualized incidence rate of AF reporting associated with exposure to 1 of 19 anticancer drugs used as monotherapy in clinical trials. The authors also report the annualized incidence rate of AF reported in the placebo arms of these trials.The authors systematically searched ClinicalTrials.gov for phase 2 and 3 cancer trials studying 19 different anticancer drugs of interest used as monotherapy, up to September 18, 2020. The authors performed a random-effects meta-analysis to compute summary AF annualized incidence rate with its 95% CI using log transformation and inverse variance weighting.A total of 191 clinical trials (47.1% were randomized) of 16 anticancer drugs across 26,604 patients were included. Incidence rates could be calculated for 15 drugs administered singly as monotherapy. Summary annualized incidence rates of AF reporting associated with exposure to 1 of the 15 anticancer drugs used as monotherapy were derived; these ranged from 0.26 to 4.92 per 100 person-years. The 3 highest annualized incidence rates of AF reporting were found for ibrutinib 4.92 (95% CI: 2.91-8.31), clofarabine 2.38 (95% CI: 0.66-8.55), and ponatinib 2.35 (95% CI: 1.78-3.12) per 100 person-years. Summary annualized incidence rate of AF reporting in the placebo arms was 0.25 per 100 person-years (95% CI: 0.10-0.65).AF reporting is not a rare event associated with anticancer drugs in clinical trials. A systematic and standardized AF detection should be considered in oncological trials, particularly those studying anticancer drugs associated with high AF rates. (Incidence of atrial fibrillation associated with anticancer drugs exposure in monotherapy, A safety meta-analysis of phase 2 and 3 clinical trials; CRD42020223710).
CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma
Authors: Hélène Asnagli, Norbert Minet, Christina Pfeiffer, Eef Hoeben, Rebecca Lane, David Laughton, Louise Birch, Geraint Jones, Andrew Novak, Andrew E. Parker, Heinz Ludwig, Alain Fischer, Sylvain Latour, Philip A. Beer
Journal: HemaSphere (2023)

Lymphoma is the most common hematological malignancy and is among the 10 most prevalent cancers worldwide. Although survival has been improved by modern immunochemotherapeutic regimens, there remains a significant need for novel targeted agents to treat both B-cell and T-cell malignancies. Cytidine triphosphate synthase 1 (CTPS1), which catalyzes the rate-limiting step in pyrimidine synthesis, plays an essential and nonredundant role in B-cell and T-cell proliferation but is complemented by the homologous CTPS2 isoform outside the hemopoietic system. This report describes the identification and characterization of CTPS1 as a novel target in B- and T-cell cancers. A series of small molecules have been developed which show potent and highly selective inhibition of CTPS1. Site-directed mutagenesis studies identified the adenosine triphosphate pocket of CTPS1 as the binding site for this small molecule series. In preclinical studies, a potent and highly selective small molecule inhibitor of CTPS1 blocked the in vitro proliferation of human neoplastic cells, showing the highest potency against lymphoid neoplasms. Importantly, pharmacological CTPS1 inhibition induced cell death by apoptosis in the majority of lymphoid cell lines tested, thus demonstrating a cytotoxic mechanism of action. Selective CTPS1 inhibition also inhibited the growth of neoplastic human B- and T- cells in vivo. These findings identify CTPS1 as a novel therapeutic target in lymphoid malignancy. A compound from this series is in phase 1/2 clinical studies for the treatment of relapsed/refractory B- and T-cell lymphoma (NCT05463263).
RBL2 Regulates Cardiac Sensitivity to Anthracycline Chemotherapy
Authors: Peng Xia, Jingrui Chen, Yadav Sapkota, Erika N. Scott, Yuening Liu, Melissa M. Hudson, Shahrad R. Rassekh, Bruce C. Carleton, Colin J.D. Ross, Eric J. Chow, Zhaokang Cheng
Journal: JACC CardioOncology (2023)

Anthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2). The aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart. Rbl2−/− mice and Rbl2+/+ littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies. The loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors. Rbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy.
Syndrome of Inappropriate Antidiuresis: From Pathophysiology to Management
Authors: Annabelle M Warren, Mathis Grossmann, Mirjam Christ-Crain, Nicholas Russell
Journal: Endocrine Reviews (2023)

Abstract Hyponatremia is the most common electrolyte disorder, affecting more than 15% of patients in the hospital. Syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of hypotonic hyponatremia, mediated by nonosmotic release of arginine vasopressin (AVP, previously known as antidiuretic hormone), which acts on the renal V2 receptors to promote water retention. There are a variety of underlying causes of SIAD, including malignancy, pulmonary pathology, and central nervous system pathology. In clinical practice, the etiology of hyponatremia is frequently multifactorial and the management approach may need to evolve during treatment of a single episode. It is therefore important to regularly reassess clinical status and biochemistry, while remaining alert to potential underlying etiological factors that may become more apparent during the course of treatment. In the absence of severe symptoms requiring urgent intervention, fluid restriction (FR) is widely endorsed as the first-line treatment for SIAD in current guidelines, but there is considerable controversy regarding second-line therapy in instances where FR is unsuccessful, which occurs in around half of cases. We review the epidemiology, pathophysiology, and differential diagnosis of SIAD, and summarize recent evidence for therapeutic options beyond FR, with a focus on tolvaptan, urea, and sodium-glucose cotransporter 2 inhibitors.
Indications for surgical resection of complicated infantile hemangiomas in the β-blocker’s era: a single-institution experience from a retrospective cohort study
Authors: Besiana P. Beqo, Paolo Gasparella, Christina Flucher, Stephan Spendel, Franz Quehenberger, Emir Q. Haxhija
Journal: International Journal of Surgery (2023)

Background and Objectives: This study aims to review how the introduction of propranolol as the primary treatment option for children with infantile hemangiomas (IHs) has affected the use of other treatment options at our institution and to determine the indications for surgical treatment of children with IHs in the propranolol era. Patients and Methods: The authors conducted a single-center, noncompeting, historical/retrospective cohort study to review all cases referred to the institution for IH evaluation from 2005 to 2020. The authors analyzed the complete charts of patients who received surgery from 2011 to 2020 and evaluated the reasons for each surgical intervention. Detailed descriptive statistics are provided. Logistic regression analysis and Pearson’s χ 2 -test were applied. Results: During the study period, 592 children received treatment. From 2011, oral propranolol ( n =268; 74%) and surgery ( n =95; 26%) were the only treatments of choice for complicated IH cases. A significant decrease in the frequency of surgical treatment was observed ( P =0.01). The authors identified four main indications for surgical treatment: (1) patients with ulceration and IH size appropriate for surgical resection (15%); (2) patients whose parents preferred surgical treatment (19%); (3) patients who presented late and underwent surgery before the age of three (29%); and (4) patients with sequelae after IH involution and excision after the third year of life (37%). Conclusions: Despite the significant decrease in the need for surgical treatment of children with IHs since the introduction of propranolol, there are still several clear indications for treating IH cases where surgery plays a crucial role.
Electronic Neurons for a New Learning Paradigm
Authors: Zhen Wang, Jiajia Wang, Xiang Shi, Zhengfeng Zhu, Peining Chen, Huisheng Peng
Journal: Advanced Healthcare Materials (2023)

Abstract Learning is the cornerstone of the growth and development of human beings. However, traditional learning methods are insufficient to meet the explosive growth of knowledge and information. Repeated training accounts for a large proportion of learning time, which significantly limits the improvement of learning efficiency. Inspired by cloud storage technology, electronic neurons (E‐neuron) with functions similar to neurons in the brain are proposed. Implanted E‐neurons can form new patterns of neural activity in circuits, including both E‐neurons and biological neurons, which can transfer knowledge from electronic cloud devices to human beings without training. Herein, the feasibility of this concept is preliminarily demonstrated. Fiber neural electrodes (FNEs) made of poly(3,4‐ethylene dioxythiophene) (PEDOT) modified carbon nanotubes (CNTs) are used to form both dendrites and axons of E‐neuron. After the implantation of an E‐neuron in a mouse's brain, an electrical neural connection is created between the mitral cell and dorsolateral periaqueductal gray (dlPAG). A piece of knowledge similar to “The red light stops; the green light is all right.” is then passed on to the mouse.
The emergence of the circulating vaccine-derived poliovirus type 2 in multiple countries requires active surveillance: current scenario and counteracting strategies
Authors: Ranjan K. Mohapatra, L.V. Simhachalam Kutikuppala, Veronique Seidel, Azaj Ansari, Snehasish Mishra, Venkataramana Kandi
Journal: International Journal of Surgery (2023)

Mohapatra, Ranjan K. MSc, MPhil, PhD; Kutikuppala, L.V. Simhachalam MBBS; Seidel, Veronique PhD; Ansari, Azaj PhD; Mishra, Snehasish PhD; Kandi, Venkataramana PhD Author Information
Impact of left ventricular ejection fraction phenotypes on healthcare resource utilization in hospitalized heart failure: a secondary analysis of <scp>REPORT‐HF</scp>
Authors: Dimitrios Farmakis, Jasper Tromp, Smaragdi Marinaki, Wouter Ouwerkerk, Christiane E. Angermann, Vasiliki Bistola, Ulf Dahlstrom, Kenneth Dickstein, Georg Ertl, Mathieu Ghadanfar, Mahmoud Hassanein, Achim Obergfell, Sergio V. Perrone, Eftihia Polyzogopoulou, Anja Schweizer, Ioannis Boletis, John G.F. Cleland, Sean P. Collins, Carolyn S.P. Lam, Gerasimos Filippatos
Journal: European Journal of Heart Failure (2023)
CERT1 mutations perturb human development by disrupting sphingolipid homeostasis
Authors: Charlotte Gehin, Museer A. Lone, Winston Lee, Laura Capolupo, Sylvia Ho, Adekemi M. Adeyemi, Erica H. Gerkes, Alexander P.A. Stegmann, Estrella López-Martín, Eva Bermejo-Sánchez, Beatriz Martínez-Delgado, Christiane Zweier, Cornelia Kraus, Bernt Popp, Vincent Strehlow, Daniel Gräfe, Ina Knerr, Eppie R. Jones, Stefano Zamuner, Luciano A. Abriata, Vidya Kunnathully, Brandon E. Moeller, Anthony Vocat, Samuel Rommelaere, Jean-Philippe Bocquete, Evelyne Ruchti, Greta Limoni, Marine Van Campenhoudt, Samuel Bourgeat, Petra Henklein, Christian Gilissen, Bregje W. van Bon, Rolph Pfundt, Marjolein H. Willemsen, Jolanda H. Schieving, Emanuela Leonardi, Fiorenza Soli, Alessandra Murgia, Hui Guo, Qiumeng Zhang, Kun Xia, Christina R. Fagerberg, Christoph P. Beier, Martin J. Larsen, Irene Valenzuela, Paula Fernández-Álvarez, Shiyi Xiong, Robert Śmigiel, Vanesa López-González, Lluís Armengol, Manuela Morleo, Angelo Selicorni, Annalaura Torella, Moira Blyth, Nicola S. Cooper, Valerie Wilson, Renske Oegema, Yvan Herenger, Aurore Garde, Ange-Line Bruel, Frederic Tran Mau-Them, Alexis B.R. Maddocks, Jennifer M. Bain, Musadiq A. Bhat, Gregory Costain, Peter Kannu, Ashish Marwaha, Neena L. Champaigne, Michael J. Friez, Ellen B. Richardson, Vykuntaraju K. Gowda, Varunvenkat M. Srinivasan, Yask Gupta, Tze Y. Lim, Simone Sanna-Cherchi, Bruno Lemaitre, Toshiyuki Yamaji, Kentaro Hanada, John E. Burke, Ana Marjia Jakšić, Brian D. McCabe, Paolo De Los Rios, Thorsten Hornemann, Giovanni D’Angelo, Vincenzo A. Gennarino
Journal: Journal of Clinical Investigation (2023)

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call CerTra syndrome. These findings uncover a central role for CERT autoregulation in the control of the sphingolipid biosynthetic flux, provide unexpected insight into the structural organisation of CERT, and suggest a possible therapeutic approach for CerTra syndrome patients.
The effectiveness and safety of oral medications, onabotulinumtoxinA (three doses) and transcutaneous tibial nerve stimulation as non or minimally invasive treatment for the management of neurogenic detrusor overactivity in adults: a systematic review and network meta-analysis
Authors: Yuanzhuo Chen, Liao Peng, Chi Zhang, Jiawei Chen, Jiahui Chen, Hong Shen, Deyi Luo
Journal: International Journal of Surgery (2023)

Background: Oral medications, onabotulinumtoxinA injections, and transcutaneous tibial nerve stimulation (TTNS) are recommended by the American Urological Association/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction guidelines as non or minimally invasive treatments for patients with neurogenic detrusor overactivity (NDO) without treatment hierarchy. Objective: The objective was to compare and rank the effectiveness and safety of oral medications, three doses of onabotulinumtoxinA, and TTNS on improving urodynamic outcomes in patient-reported outcomes and safety outcomes in patients with NDO. Methods: The authors searched PubMed, EMBASE, MEDLINE, Cochrane Library, Medicine, and clinicaltrials.gov, from their inception to October 2022 and included randomized controlled studies on the drug, onabotulinumtoxinA, and TTNS for the treatment of patients with NDO. Outcomes included urodynamic parameters, voiding diary, quality of life changes, adverse event rate and postvoid residual. Results: A total of 26 articles and 2938 patients were included in the statistics. Regarding effectiveness, all interventions except TTNS and α-blockers were statistically different for the placebo group. The urodynamic outcome and patient-reported outcome suggested that onabotulinumtoxinA injection (urodynamic outcome: onabotulinumtoxinA 200 U, the mean surface under the cumulative ranking curve (SUCRA): 87.4; patient-reported outcome: onabotulinumtoxinA 100 U, mean SUCRA: 89.8) was the most effective treatment, and the safety outcome suggested that TTNS (SUCRA: 83.3) was the safest. Cluster analysis found that antimuscarinics and β3-adrenoceptor-agonists possessed good effectiveness and safety. Conclusion: OnabotulinumtoxinA injection is probably the most effective way to treat patients with NDO, with increasing effectiveness but decreasing safety as the dose rises. The effectiveness of α-blockers and TTNS was not statistically different from the placebo group. Antimuscarinics and β3-adrenoceptor-agonists have good effectiveness and safety.
Specific Spleen‐Accumulated NIR‐II Fluorescent Probe for Imaging‐Guided Splenic Operation
Authors: Yiqing Yang, Diankai Liu, Zixu He, Xiaofan Zhang, Huihui Liu, Xiaohua Li, Huimin Ma, Wen Shi
Journal: Advanced Healthcare Materials (2023)

Spleen is a large immune organ in the body. Splenic operations such as splenectomy and intrasplenic injection are of paramount importance for immunological research and splenic diseases. Fluorescence imaging can vastly simplify these operations, but a specific spleen-targeting probe is still unavailable. Herein, the first specific spleen-accumulated fluorescent probe, VIX-S is reported, which fluoresces at 1064 nm and is highly stable. Systematic studies reveal the superior targeting and imaging performance of VIX-S for the spleen in both nude and haired mice. In vivo imaging indicates that the probe can image the morphology of spleen with a signal-background ratio of at least two-fold higher than that of the liver. Moreover, the application of VIX-S in imaging-guided splenic operation, including splenic injury and intrasplenic injection, is demonstrated, which may provide a practice tool for spleen research in the animal model.
Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist
Authors: David P. Nichols, Sarah J. Morgan, Michelle Skalland, Anh T. Vo, Jill M. Van Dalfsen, Sachinkumar B.P. Singh, Wendy Ni, Lucas R. Hoffman, Kailee McGeer, Sonya L. Heltshe, John P. Clancy, Steven M. Rowe, Peter Jorth, Pradeep K. Singh
Journal: Journal of Clinical Investigation (2023)

BACKGROUND. Lung infections are among the most consequential manifestations of cystic fibrosis (CF) and are associated with reduced lung function and shortened survival. Drugs called CFTR modulators improve activity of dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) channels, which is the physiological defect causing CF. However, it is unclear how improved CFTR activity affects CF lung infections.